Upon stimulation by antigen, naïve CD4+ T helper cells develop into two main effector pathways, Th1 and Th2 cells, defined by their cytokine profiles (Mosmann et al. J Immunol 136, 2348-2357 (1986), Mosmann et al. Immunol Today 19, 138-146 (1996), Abbas, et al. Nature 383, 787-793 (1996)).
Th1 cells produce cytokines (interferon (IFN-γ, interleukin (IL)-2, tumor-necrosis factor TNF-α and lymphotoxin) that are most frequently associated with cell-mediated immune responses against intracellular pathogens. The pathological consequences of an inappropriate Th1 response are delayed type hypersensitivity (DTH) reactions (Sher, et al. Annu Rev Immunol. 10, 385-409 (1992)), induction of organ-specific autoimmune disease (Liblau, et al. Immunol Today 16, 34-38 (1995)), rheumatoid arthritis, inflammatory bowel disease (IBD), type I diabetes multiple sclerosis, and allograft rejection.
Th2 cells produce cytokines (IL-4, IL-10 and IL-13) necessary for the clearance of extracellular helminthic infections, and inappropriate Th2 cell activation promotes the onset of atopic and allergic diseases (Abbas, et al. Nature 383, 787-793 (1996), Sher, et al. Annu Rev Immunol. 10, 385-409 (1992)), such as allergic asthma.
In addition to their distinct roles in disease, the two T helper subsets also cross-regulate each other's expansion and functions. Thus, preferential induction of Th2 cells inhibits autoimmune diseases (Nicholson, L., et al. Immunity 3, 397-405 (1995), Kuchroo, et al. Cell 80, 707-718 (1995)), while predominant induction of Th1 cells can regulate asthma, atopy and allergies (Lack, et al. J Immunol 152, 2546-2554 (1994); Hofstra, et al. J Immunol 161, 5054-5060 (1998)).
Applicants have recently identified a novel cell surface protein, Tim-3, which is expressed on Th1 but not Th2 cells. Tim-3 (T cell Immunoglobulin and Mucin domain containing molecule) is a type I membrane protein of 281 amino acids whose extracellular domain comprises of an IgV-like domain followed by a mucin-like region. The human orthologue of Tim-3 shares 63% amino acid identity with murine Tim-3. Tim-3 is polymorphic and, along with other Tim family members, has been linked to murine asthma (McIntire, J. et al. Nat Immunol 2, 1109-1116 (2001)). In addition, the Tim gene family region is syntenic with a major asthma susceptibility locus in humans (McIntire, J. et al. Nat Immunol 2, 1109-1116 (2001)). These studies underscore the importance of Tim-3 and the Tim gene family in regulation of immune-mediated diseases.
In vivo during an ongoing immune response, administration of anti-Tim-3-antibody increased macrophage activation and expansion (Monney, L. et al. Nature 415, 536-541 (2002). Anti-Tim-3 antibody treatment also exacerbated the autoimmune disease experimental autoimmune encephalomyelitis (EAE), significantly increasing mortality and causing enhanced demyelination and infiltration of activated macrophages to the central nervous system (CNS).
Accordingly, a need remains to identify agents which modulate tim-3 function and thus modulate immune responses. Some aspects of the present invention provide such agents, methods to identify such agents, and methods of modulating immune responses using such agents.